HIV-associated osteopenia is a recently recognized health problem. Both HIV-infected men and women are affected. In a recent study among a group of HIV-infected men, subjects taking protease inhibitors had more than double the risk of osteopenia and osteoporosis as compared with subjects not receiving protease inhibitors. In addition, HIV-infected women and women with AIDS wasting have significantly reduced bone density as compared to age and weight-similar healthy controls. Furthermore, significant morbidity associated with osteopenia has been reported in this population. The prevalence of this disease has been estimated as high as 67.5% in some HIV infected groups. Bisphosphonates have been widely used for treating osteoporosis and have been demonstrated to increase bone mineral density and reduce the rate of fracture. A recent study using intravenous zoledronate, a third-generation bisphosphonate, in postmenopausal women with osteopenia demonstrated beneficial improvements in bone density and significant reductions in bone resorption up to one year after single intravenous zoledronate dosing. Given the assurance of treatment delivery with single intravenous dosing and long-term health benefits, zoledronate appears to be an ideal treatment regimen for osteopenic HIV-infected subjects with complicated medical treatment regimens and medical compliance issues. We propose a double-blinded, placebo-controlled, randomized controlled trial to evaluate the effectiveness of intravenous zoledronate in HIV-infected subjects with osteopenia. We will determine whether zoledronate increases bone density and reduces ongoing bone loss in subjects with HIV-associated osteopenia. Long-term outcomes will include whether zoledronate reduces the risk of vertebral fracture and other osteopenia-associated morbidities in HIV-infected subjects. Given the polypharmacy often present in HIV-infected patients, we will also closely monitor the safety of zoledronate therapy and potential drug interactions in subjects on antiretroviral therapy. Finally, data generated by this pilot study will lay the foundation for future studies of bisphosphonate therapy in HIV-infected persons with bone disease.